FR2940910A1 - NEW S-ADENOSYL-METHIONINE COMPRESSOR - Google Patents

Abstract

The invention relates to a tablet for pharmaceutical use, particularly for veterinary use particularly well suited to the chronic treatment of liver failure comprising at least one salt of S-Adenosyl-Methionine. Said tablet has the advantage of being breakable and able to integrate an appetite.

Description

The invention relates to a tablet for pharmaceutical use, particularly for veterinary use. Said tablet is particularly well suited to the chronic treatment of hepatic insufficiency.

S-Adenosyl-Methionine (SAMe) salts are often indicated for the chronic treatment of hepatic insufficiency.

They are very hygroscopic compounds and therefore difficult to manipulate outside controlled hygrometry chamber. Indeed, in the presence of moisture they gorge themselves with water and become difficult to manipulate, taking the texture of an eraser.

The tablets of the prior art are coated, generally with a gastro-resistant coating to prevent heartburn and the dyspepsia they cause. This presents different problems.

When it is desired to cut these cut tablets, the salts at the cutting surface are no longer coated and then take the texture of a

15 gum. Thus, because of the gastro-resistant coating, the tablets are unscrewable.

In addition, because of the enteric coating, they can not contain appetites.

It is therefore easy to understand that there is a need for breakable tablets

Including S-Adenosyl-Methionine salts, in which adjuvants, for example, one or more appetite (s), may further be added. In addition, since these S-Adenosyl-Methionine salts cause heartburn and dyspepsia, one of the other objects of the invention is to provide scored tablets comprising S-Adenosyl-Methionine salts which furthermore avoid the

25 heartburn and dyspepsia. Finally, another object of the invention is to provide a breakable tablet comprising salts of S-Adenosyl-Methionine whose active ingredient will be released in a manner independent of the pH.

In order to solve these various problems, the inventors have developed a breakable tablet comprising S-Adenosyl-Methionine salts whose

30 elementary particles are coated with at least one neutral polymer and insoluble in water.

Elementary particles are understood to mean each fine or extra fine particle or grain or granule of the pure active compound, whether or not it is fixed on a support.

It is thus understood that according to the invention, the elementary particles of the S-Adenosyl-Methionine salts are coated with at least one neutral and water-insoluble polymer, before being subjected to pressure to take the form of a compressed Thus the final tablet is composed of particles (fine particle or extra fine, or grain or granule of the pure active compound) each coated with at least one neutral polymer and insoluble in water.

The invention therefore firstly relates to a breakable tablet comprising at least one S-Adenosyl-methionine salt and at least one neutral and water-insoluble polymer, said elementary particles of said S-Adenosyl-Methionine salt being individually coated by the neutral polymer and insoluble in water.

According to the invention, the S-Adenosyl-Methionine salts that can be used can be chosen from all the salts known to those skilled in the art, particularly S-Adenosyl-Methionine Paratoluene Sulfonate, SAdenosyl-Methionine Paratoluene sulfate and S-Adenosyl-Methionine. Adenosyl-Methionine tosylate disulfate. Preferably, according to the invention, S-Adenosyl-Methionine Paratoluene Sulfonate is used.

According to one particular embodiment of the invention, the S-Adenosyl-methionine salt may be present in the tablet in an amount of pure active material of between 20% and 70%, preferably between 25% and 55% by weight. total tablet. Those skilled in the art will easily be able to adapt the amount of commercial S-Adenosyl-Methionine salts to be used, it being understood that this is a product which is never marketed pure.

According to the invention, the elementary particles of the S-Adenosyl-Methionine salts may have a minimum size of 50 microns. The skilled person knows that in this matter there is theoretically no maximum size.

According to the invention, a neutral and water-insoluble polymer is a polymer which does not react chemically with the active ingredient and whose solubility in water does not exceed 100 μg / ml (reference US Pharmacopoeia (United States Pharmacopeia ( USP) # 24 NF19) United States Pharmacopeia Editor, 25th edition (January 1, 2000)).

The neutral and water-insoluble polymer can essentially be used as a barrier membrane. It may be chosen to control the release of the S-Adenosyl-Methionine salt throughout the digestive tract, advantageously in a pH-independent manner. The release of S-Adenosyl-Methionine will then be a function of its diffusion through said neutral and insoluble polymer in water.

In addition, it allows taste masking of the highly effective S-Adenosyl-Methionine salts, which represents another advantage of the invention.

Among the neutral and water-insoluble polymers that may be used according to the invention, mention may be made of celluloses such as methylcellulose, ethylcellulose, hydromellose, phthalate, cellulose acetate phthalate or methacrylates. According to the invention, ethylcellulose is preferably used.

According to one particular embodiment of the invention, the neutral and water-insoluble polymer may be present in the tablet in an amount of between 25% and 50%, preferably between 30% and 40% by weight, relative to the active ingredient. .

According to another embodiment of the invention, the tablet may further comprise an alkaline substance which makes it possible, on the one hand, to improve the stability of S-Adenosyl-Methionine and / or on the other hand to protect the stomach from acid attacks caused by S-Adenosyl-Methionine salts.

The term "alkaline substance" according to the invention means a compound which in solution has a pH strictly greater than 7.

Thus, when the tablet is administered, the gastric juice may dissolve as the alkaline substance and S-Adenosyl-Methionine simultaneously. The diffusion of the S-Adenosyl-Methionine salts from the tablet may thus be accompanied by the diffusion of the dissolved alkaline substance, which may make it possible to reduce the acidic and aggressive effect of the S-Adenosyl-Methionine salts with respect to -vis of the stomach.

According to the invention, the alkaline substance may advantageously be selected from magnesium oxide, sodium bicarbonate, potassium bicarbonate or aluminum hydroxide. Preferably, according to the invention, magnesium oxide will be used. Of course, the alkaline substance may comprise several of these compounds in a binary mixture, ternary, etc.

The amount of alkaline material usable per tablet may be determined to meet the "Acid neutralizing capacity" tests described in the US Pharmacopea (page 1863, 301).

According to the invention, the tablet may further comprise, simultaneously or individually,

an appetite compound such as, for example, a product of biological origin (liver powder, meat, fish, etc.) or vegetable powder and preferably a powder of plant origin, in an amount of between 1% and 50%, preferably between % and 30% based on the total weight of the tablet; a neutral diluent / excipient such as, for example, lactose, manitol,

microcrystalline cellulose, starch and its derivatives, sugars and preferably lactose or microcrystalline cellulose, in an amount of between 10% and 70%, preferably between 30% and 60% relative to the total weight of the tablet; a flow agent, such as, for example, silica, stearate derivatives and any other agent known to those skilled in the art that may be included in the composition of a tablet and preferentially silica, in a minimum amount of 0.1 % based on the total weight of the tablet; a disintegrant, such as, for example, povidone derivatives or crospovidone, preferably crospovidone, in a minimum amount of 0.5% relative to the total weight of the tablet; and any excipient which can, according to the skilled person, enter into the composition of a tablet (eg lubricant).

The invention also relates to the process for producing the tablet 25 according to the invention.

According to a first variant of the process according to the invention, in a first step, the S-Adenosyl-Methionine salt is granulated by spraying with an aqueous solution of S-Adenosyl-Methionine salt in the presence of at least one neutral excipient, on which elementary particles

S-Adenosyl-Methionine salt will settle and dry.

In a second step, the granules obtained in the first step are coated with a solution comprising at least one neutral and insoluble polymer in water. The coating techniques that can be used in the second step are those that are well known to those skilled in the art and advantageously the one described in the experimental part of the "coating" paragraph of Example 1 will be used.

In a third step, the tablets according to the invention are produced according to the usual tableting techniques. At this stage it is possible to use only coated granules obtained in the second step, alone or in the presence of at least one other excipients usually used in the pharmacy, for example chosen from a phospholipid, a diluent, a flow agent , an appetite, a disintegrator, a lubricant.

Advantageously according to the invention, the tablets will comprise at least in addition to the coated granules obtained in the second step, an alkaline substance, as defined above.

According to the process of the invention, the granulation step can be carried out by spraying a solution of S-Adenosyl-Methionine salt in a fluidized air bed according to the usual techniques in this field, on at least one neutral excipient.

According to the invention, the neutral excipient may be for example microcrystalline cellulose, lactose fine crystals, manitol or maltodextrin, preferably microcrystalline cellulose, in an amount of between 30% and 60% relative to to the total weight of the tablet.

In this variant, the amount of salt may represent from 20% to 80%, preferably from 50% to 70%, relative to the total amount represented by the amount of salt added with the total amount of neutral excipient, by weight .

According to a second variant of the process according to the invention, in a first step, an aqueous solution of S-Adenosyl-Methionine salt is sprayed in, for example, a hot chamber so that, during spraying, the solution dries almost instantaneously and that only persists a powder of elementary particles of S-Adenosyl-Methionine salt, in a second step is coated as above, the elemental particles of S-Adenosyl-Methionine salt obtained in the first step with a solution comprising at least one neutral and insoluble polymer in water and in a third step the tablets according to the invention are produced according to the usual tableting techniques.

At this stage it is possible to use only coated granules obtained in the second step, alone or in the presence of at least one other excipients usually used in the pharmacy, for example chosen from a phospholipid, a diluent, a flow agent , an appetite, a disintegrator, a lubricant.

Advantageously according to the invention, the tablets will comprise at least in addition to the coated granules obtained in the second step, an alkaline substance, as defined above.

According to the invention, the salt solution used in the first step of the process 10 is a salt solution prepared at a concentration which may be between 10 to 60% w / w, preferably 20 to 50%.

According to the process of the invention, the amount of coating may represent from 10 to 20% by weight, relative to the total weight of granules obtained in step 1 plus the coating weight.

The tablet obtained after the implementation of one of the methods according to the invention is particularly well suited to the chronic treatment of hepatic insufficiency. It has an attenuated acidity so as not to cause gastric hyperacidity and is therefore not aggressive for the stomach. It can furthermore include an appetite and is breakable.

It also has the advantage of releasing the active ingredient in a pH-independent manner.

The subject of the invention is also the use of a tablet according to the invention as a medicament.

The invention also relates to the use of a tablet according to the invention, for the preparation of a medicament for the treatment or prevention of chronic renal failure.

The invention is usable in mammals, especially in humans, preferably in animals, especially in small animals such as dogs and cats.

The following examples illustrate but do not limit the present application.

Example 1 Preparation of Tablets The preparation of a coated tablet containing SAM-e Paratoluene Sulfonate is carried out in two steps: a granulation step followed by a coating step.

1. Step of adsorption of SAM-e Paratoluene sulfonate on an inert support An aqueous solution of SAM-e Paratoluene Sulfonate (26 to 50% w / w) is sprayed in a fluidized air bed on a mixture of neutral excipients comprising microcrystalline cellulose and lactose fine crystals according to the proportions given in the table below. Components Proportions 1 SAMe paratoluene sulfonate * 60.00 Lactose Fine Crystals 10.00 Microcrystalline Cellulose PH102 30.00 TOTAL 100.00 * The SAM-e Paratoluene Sulfonate is in aqueous solution at approximately 50%. 2. Coating The powder obtained previously is then coated. For this step, neutral and water-insoluble polymers were used such as cellulose derivatives such as ethylcellulose. The spraying method using a fluidized air bed (GLATT type) (well known from the prior art), at a temperature compatible with the neutral polymer used for the coating, for a variable duration depending on the quantities, and batch size will be used for this step. The three formulas are prepared according to the proportions given in the table below (in%). Components Formula N ° 1 Formula N ° 2 Form N ° 3 * Internal phase 85,00 90,00 81,00 Ethylcellulose 15,00 10.00 19,00 TOTAL 100, 00 100, 00 100, 00 20 * formulas n ° 1 and 2 were made with a single coating contrary to the formula No. 3 which has undergone two successive coatings (the number of coating is a function of the content of SAM-e and palatability results). 3. Final Mixing The table below presents several standard formulations of tablets according to the invention: Components Composition Composition Composition SAM-e N ° 1 SAM-e N ° 2 SAM-e N ° 3 Grain coated with SAM-e ** 67.44 76.65 67.44 Silybin / phospholipids 0.00 0.00 4.76 Thinner (lactose, cellulose 17.81 8.60 13.05 microcrystalline ...) Flow Agent 1.00 1.00 1.00 (silica ...) Alkaline (oxide 1.25 1.25 1.25 Mg ...) Appetizer 5.00 5.00 5.00 Disintegrating (Acdisol, 7.00 7.00 7.00 crospovidone ...) Lubricant (Pruv ...) 0.50 0.50 0.50 TOTAL 100.00 100.00 100.00 **: obtained in step 2. 4. Pharmacokinetic tests To confirm the results obtained in vitro, pharmacokinetic tests were performed on dogs. The results showed that SAMe is absorbed into the stomach immediately after administration and is not degraded. The pharmacokinetic profiles of the different dogs are homogeneous and very little variable.

To check the effectiveness of taste masking palatability tests were conducted on dogs and cats. The results showed a significant improvement in palatability.

Claims (17)

1. A breakable tablet comprising at least elementary particles of S-Adenosyl-methionine salt and at least one neutral and water-insoluble polymer, said elementary particles being individually coated with the neutral polymer and insoluble in water. 2.) Tablet according to claim 1, characterized in that the salt of SAdenosyl-Methionine is chosen from S-Adenosyl-Methionine Paratoluene Sulfonate, S-Adenosyl-Methionine Paratoluene sulfate and S-Adenosyl-Methionine tosylate disulfate, preferably S-Adenosyl-Methionine Paratoluene Sulfonate. 3. Tablet according to any one of claims 1 or 2, characterized in that the salt of S-Adenosyl-Methionine present in the tablet is in an amount of pure active material of between 20% and 70%, preferably between 25% and 70%. % and 55% of the total weight of the tablet. 4.) Tablet according to any one of claims 1 to 3, characterized in that the neutral and water-insoluble polymer is chosen from celluloses, such as methylcellulose, ethylcellulose, hydromellose, phthalate, acetate phthalate cellulose or methacrylates, preferably ethylcellulose. 5. Tablet according to any one of claims 1 to 4, characterized in that the neutral polymer and insoluble in water is present in the tablet in an amount of between 25% and 50%, preferably between 30% and 40%. % by weight relative to the active ingredient. 6. Tablet according to any one of claims 1 to 5, characterized in that the tablet further comprises alkaline substance. 7.) Tablet according to claim 6, characterized in that the alkaline substance selected from magnesium oxide, sodium bicarbonate, potassium bicarbonate or aluminum hydroxide preferentially magnesium oxide. 8. Tablet according to any one of claims 1 to 7, characterized in that it further comprises simultaneously or individually, an appetite compound such as a product of biological origin (liver powder, meat, fish. ..) or vegetable and preferentially a plant-based powder in an amount of between 1% and 50%, preferably between 3% and 30% relative to the total weight of the tablet; a neutral diluent / excipient such as, for example, lactose, manitol, microcrystalline cellulose, starch and its derivatives, sugars and preferably lactose or microcrystalline cellulose, in an amount of between 10% and 70%, preferably between 30% and 70%; % and 60% based on the total weight of the tablet; a flow agent, such as, for example, silica, stearate derivatives and any other agent known to those skilled in the art that may be included in the composition of a tablet and preferentially silica, in a minimum amount of 0.1 % based on the total weight of the tablet; a disintegrant, such as, for example, povidone derivatives. and preferably crospovidone, in a minimum amount of 0.5% relative to the total weight of the tablet; and any excipient which can, according to one skilled in the art, enter into the composition of a tablet (eg lubricant. 9.) A method of producing a tablet according to any one of claims 1 to 8, characterized in that in a first step is carried out a granulation of S-Adenosyl-Methionine salt by spraying an aqueous solution of S-Adenosyl-Methionine salt in the presence of at least one neutral excipient; in a second step, the granules obtained in the first step are coated with a solution comprising at least one neutral and insoluble polymer in water; in a third step, the tablets according to the invention are produced. 10.) A method according to claim 9, characterized in that the neutral excipient is microcrystalline cellulose, lactose fine crystals, manitol, or maltodextrin, preferably microcrystalline cellulose, in an amount between 30% and 60% based on the total weight of the tablet. 11. The process as claimed in claim 9, wherein the amount of salt may represent from 20% to 80%, preferably from 50% to 70%, relative to the total amount represented by the amount of the total amount of neutral carrier, by weight, added 12) A method of producing a tablet according to any one of claims 1 to 8, characterized in that in a first step is carried out a spraying of an aqueous solution of S-Adenosyl-Methionine salt to obtain a powder of elementary particles of SAdenosyl-Methionine salt, in a second step, said elemental salt particles of S-Adenosyl-Methionine obtained in the first step are coated with a solution comprising at least one neutral and insoluble polymer in water and in a third step, the tablets according to the invention are produced. 13. A process according to any one of claims 9 to 12, characterized in that in the third step, the tablets comprise coated granules obtained in the second step, alone or in the presence of at least one of the other excipients usually used. in the pharmacy, for example chosen from a phospholipid, a diluent, a flow agent, an appetite, a disintegrant, a lubricant. 14. A method according to any one of claims 9 to 12, characterized in that the salt solution used in the first step is an aqueous solution of salt whose concentration is between 10 to 60% w / w, preferably of 20 to 50%. 15) Process according to any one of claims 9 to 14, characterized in that the amount of coating represents from 10 to 20% by weight, relative to the total weight of granules obtained in step 1, plus the weight of 'coating. 16) Use of a tablet according to any one of claims 1 to 9 as a medicament. 17) Use of a tablet according to any one of claims 1 to 9 for the preparation of a medicament for the treatment or prevention of chronic renal failure.